Phenylamino-benzoxazole substituted carboxylic acids, method for their production and use thereof as medicaments

ABSTRACT

This invention relates to a compound of formula I, 
     
       
         
         
             
             
         
       
     
     wherein R1, R2, R6, R7, R8, R9, R10, m and X are as defined herein, or a physiologically tolerated salt thereof, its pharmaceutical composition and use for lowering blood glucose, treating diabetes, or increasing insulin release.

This application is a Continuation of International Application No.PCT/EP2007/003806, filed Apr. 30, 2007, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to phenylaminobenzoxazole-substituted carboxylicacids and their physiologically tolerated salts.

BACKGROUND OF THE INVENTION

Compounds of similar structure have been described in the prior art (seeWO 94/08962).

The invention was based on the object of providing compounds whichdisplay a therapeutically utilizable effect. The object was inparticular to find novel compounds suitable for the treatment ofhyperglycemia and diabetes.

SUMMARY OF THE INVENTION

The invention therefore relates to compounds of the formula I,

in which the meanings are

-   R1 H or (C₁-C₆)-alkyl;-   R6, R7, R8, R9, R10, independently of one another H, F, Cl, Br, CN,    CF₃, OH, OCF₃, OCHF₂, SCH₃, SCF₃, phenyl, Ophenyl, COOH,    COO—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-allyl,    OBn, SO₃H, SO₂NR3R4, NR3R4 or SO₂—N-piperidinyl, where alkyl and    phenyl may be substituted one or more times by R2, and where in each    case two of the radicals R6, R7, R8, R9, R10, in adjacent position    on the phenyl ring may together form a radical —O—CH₂—O—,    —O—(CH₂)₂—O— or —CH═CH—CH═CH—;-   m 0, 1, 2 or 3;-   X bond, (C₂-C₁₀)-alkylene, (C₃-C₁₂)-cycloalkyl,    (C₁-C₈)-alkylene-(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkylene,    (C₁-C₈)-alkylene-(C₃-C₁₂)-cycloalkyl,    (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkylene,    (C₂-C₈)-alkenylene-(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkylene,    (C₁-C₈)-alkylene-(C₃-C₁₂)-cycloalkyl-(C₂-C₈)-alkenylene,    (C₂-C₈)-alkenylene-(C₃-C₁₂)-cycloalkyl,    (C₃-C₁₂)-cycloalkyl-(C₂-C₈)-alkenylene, (C₂-C₁₀)-alkenylene or    (C₂-C₁₀)-alkynylene, where alkylene, cycloalkyl, alkenylene and    alkynylene may be substituted one or more times by R5;-   R2 OH, F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where alkyl may be substituted one or more times by    OH, F, Cl, Br or CN;-   R3, R4 independently of one another H or (C₁-C₆)-alkyl, where alkyl    may be substituted one or more times by OH, F, Cl or Br;-   R5 NH₂, NH(C₁-C₄)-alkyl, N[(C₁-C₄)-alkyl]₂, F, Cl, Br, CN, OH,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl or (C₂-C₆)-alkynyl;    and the physiologically tolerated salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Preference is given to compounds of the formula I in which one or moreradicals have the following meanings:

-   R1 H or (C₁-C₆)-alkyl;    R6, R7, R8, R9, R10, independently of one another H, F, Cl, Br, CF₃,    OCH₃, OCF₃, OCHF₂, SCH₃, SCF₃, phenyl, (C₁-C₆)-alkyl,    O—(C₁-C₆)-alkyl or NR3R4, where alkyl and phenyl may be substituted    one or more times by R2, and where in each case two of the radicals    R6, R7, R8, R9, R10 in adjacent position on the phenyl ring may    together form a radical —CH═CH—CH═CH—;-   m 0;-   X (C₂-C₁₀)-alkylene, where alkylene may be substituted one or more    times by R5;-   R3, R4 independently of one another H or (C₁-C₆)-alkyl;-   R5 NH₂, NH(C₁-C₄)-alkyl, N[(C₁-C₄)-alkyl]₂, F, Cl, Br, CN, OH,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl or (C₂-C₆)-alkynyl;    and the physiologically tolerated salts thereof.

Particular preference is given to compounds of the formula I in whichone or more radicals have the following meanings:

R1 H;

R6, R7, R8, R9, R10, independently of one another H, F, Cl, Br, CF₃,OCH₃, OCF₃, OCHF₂, SCH₃, SCF₃, phenyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl orNR3R4, where alkyl and phenyl may be substituted one or more times byR2, and where in each case two of the radicals R6, R7, R8, R9, R10 inadjacent position on the phenyl ring may together form a radical—CH═CH—CH═CH—;

-   0, 1, 2 or 3;-   X —(CH₂)₂—;-   R2 F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where alkyl may be substituted one or more times by    OH, F, Cl, Br or CN;-   R3, R4 independently of one another H or (C₁-C₆)-alkyl;    and the physiologically tolerated salts thereof.

If radicals or substituents may occur more than once in the compounds ofthe formulae I, they may all independently of one another have thestated meaning and be identical or different.

The alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynyleneradicals in the radicals X, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10may be either straight-chain or branched.

The invention relates to compounds of the formula I in the form of theirsalts, racemates, racemic mixtures and pure enantiomers, anddiastereomers and mixtures thereof.

Physiologically tolerated salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have aphysiologically tolerated anion or cation. Suitable physiologicallytolerated acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, andorganic acids such as, for example, acetic acid, benzenesulfonic,benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,isethionic, lactic, lactobionic, maleic, malic, methanesulfonic,succinic, p-toluenesulfonic and tartaric acids. The chlorine salt isparticularly preferably used for medical purposes.

Suitable physiologically tolerated basic salts are ammonium salts,alkali metal salts (such as sodium and potassium salts), alkaline earthmetal salts (such as magnesium and calcium salts), zinc salts, and saltsof trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine,lysine, arginine, choline, meglumine or ethylenediamine salts.

Salts with a physiologically untolerated anion or cation likewise belongwithin the framework of the invention as useful intermediates forpreparing or purifying physiologically tolerated salts and/or for use innontherapeutic, for example in vitro applications.

A further aspect of this invention are prodrugs of the compounds of theinvention. Such prodrugs can be metabolized in vivo to a compound of theinvention. These prodrugs may themselves be active or not.

The compounds of the invention may also exist in various polymorphousforms, e.g. as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds according to the invention belongwithin the framework of the invention and are a further aspect of theinvention.

All references to “compound(s) of formula (I)” hereinafter refer tocompound(s) of the formula (I) as described herein, and the salts andsolvates thereof as described herein.

The compounds of the formula (I) and the physiologically tolerated saltsthereof represent ideal pharmaceuticals for the treatment of elevatedlipid concentrations in the blood, the metabolic syndrome, diabetes,insulin resistance, dysregulation of LDL, HLD and VLDL or cardiovasculardisorders and lipid metabolism disorders, especially hyperlipidemia. Thecompound(s) of the formula (I) can also be administered in combinationwith further active ingredients.

The amount of a compound of formula (I) necessary to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) perday and per kilogram of body weight, for example 0.1-10 mg/kg/day.Tablets or capsules may contain, for example, from 0.01 to 100 mg,typically from 0.02 to 50 mg. For the prophylaxis or therapy of theabovementioned conditions, the compounds of formula (I) may be used asthe compound itself, but they are preferably in the form of apharmaceutical composition with an acceptable carrier. The carrier must,of course, be acceptable in the sense that it is compatible with theother ingredients of the composition and is not harmful for thepatient's health. The carrier may be a solid or a liquid or both and ispreferably formulated with the compound as a single dose, for example asa tablet, which may contain from 0.05% to 95% by weight of the activeingredient. Other pharmaceutically active substances may likewise bepresent, including other compounds of formula (I). The pharmaceuticalcompositions of the invention can be produced by one of the knownpharmaceutical methods, which essentially consist of mixing theingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions of the invention are those suitable for oraland peroral (for example sublingual) administration, although the mostsuitable mode of administration depends in each individual case on thenature and severity of the condition to be treated and on the nature ofthe compound of formula (I) used in each case. Coated formulations andcoated slow-release formulations also belong within the framework of theinvention. Preference is given to acid- and gastric juice-resistantformulations. Suitable coatings resistant to gastric juice comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, suckabletablets or tablets, each of which contains a defined amount of thecompound of formula (I); as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula (I) with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Combinations with Other Medicaments

The compounds of the invention can be administered alone or incombination with one or more further pharmacologically active substanceswhich have, for example, beneficial effects on metabolic disturbances ordisorders frequently associated therewith. Examples of such medicamentsare

-   -   1. medicaments which lower blood glucose, antidiabetics,    -   2. active ingredients for the treatment of dyslipidemias,    -   3. antiatherosclerotic medicaments,    -   4. antiobesity agents,    -   5. antiinflammatory active ingredients    -   6. active ingredients for the treatment of malignant tumors    -   7. antithrombotic active ingredients    -   8. active ingredients for the treatment of high blood pressure    -   9. active ingredients for the treatment of heart failure and    -   10. active ingredients for the treatment and/or prevention of        complications caused by diabetes or associated with diabetes.

They can be combined with the compounds of the invention of the formulaI in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Further examples of active ingredients suitable for combination productsare in particular: All antidiabetics which are mentioned in the RoteListe 2006, chapter 12; all weight-reducing agents/appetite suppressantswhich are mentioned in the Rote Liste 2006, chapter 1; alllipid-lowering agents which are mentioned in the Rote Liste 2006,chapter 58. They may be combined with the compound of the invention ofthe formula I in particular for a synergistic improvement in the effect.The active ingredient combination can be administered either by separateadministration of the active ingredients to the patient or in the formof combination products in which a plurality of active ingredients ispresent in a pharmaceutical preparation. Most of the active ingredientsmentioned hereinafter are disclosed in the USP Dictionary of USAN andInternational Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives such as, forexample, Lantus® (see www.lantus.com) or HMR 1964 or those described inWO2005005477 (Novo Nordisk), fast-acting insulins (see U.S. Pat. No.6,221,633), inhalable insulins such as, for example, Exubera® or oralinsulins such as, for example, IN-105 (Nobex) or Oral-lyn™ (GenerexBiotechnology), GLP-1 derivatives such as, for example, exenatide,liraglutide or those which have been disclosed in WO98/08871 orWO2005027978 of Novo Nordisk A/S, in WO01/04156 of Zealand or inWO00/34331 of Beaufour-Ipsen, pramlintide acetate (Symlin; AmylinPharmaceuticals), and orally effective hypoglycemic active ingredients.

The orally effective hypoglycemic active ingredients include preferablysulfonylureas,

biguanidines,meglitinides,oxadiazolidinediones,thiazolidinediones,glucosidase inhibitors,inhibitors of glycogen phosphorylase,glucagon antagonists,glucokinase activators,inhibitors of fructose-1,6-bisphosphatase,modulators of glucose transporter 4 (GLUT4),inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),GLP-1 agonists,potassium channel openers such as, for example, those which have beendisclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S,inhibitors of dipeptidylpeptidase IV (DPP-IV),insulin sensitizers,inhibitors of liver enzymes involved in stimulating gluconeogenesisand/or glycogenolysis,modulators of glucose uptake, of glucose transport and of glucosereabsorption,inhibitors of 11β-HSD1,inhibitors of protein tyrosine phosphatase 1B (PTP1B),modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1,SGLT2),compounds which alter lipid metabolism such as antihyperlipidemic activeingredients and antilipidemic active ingredients,compounds which reduce food intake,compounds which increase thermogenesis,PPAR and RXR modulators andactive ingredients which act on the ATP-dependent potassium channel ofthe beta cells.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an HMGCoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin or L-659699.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol absorption inhibitor suchas, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692), MD-0727 (Microbia Inc., WO2005021497) or with compoundsas described in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.),WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483 orCS-011 (rivoglitazone).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist such as, forexample, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist suchas, for example, muraglitazar, tesaglitazar, naveglitazar, LY-510929,ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as described inPCT/US 00/11833, PCT/US 00/11490, DE10142734.4 or in J. P. Berger etal., TRENDS in Pharmacological Sciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist such as, forexample, GW-501516.

In one embodiment of the invention, the compound of the formula I isadministered in combination with metaglidasen or with MBX-2044 or otherpartial PPAR gamma agonists/antagonists.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate such as, for example,fenofibrate, clofibrate or bezafibrate.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an MTP inhibitor such as, for example,implitapide, BMS-201038, R-103757 or those described in WO2005085226.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor such as, for example,torcetrapib or JTT-705.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 orWO00/61568), such as, for example, HMR 1741 or those as described in DE10 2005 033099.1 and DE 10 2005 033100.9.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorbent suchas, for example, cholestyramine or colesevelam.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), such as, for example, HMR1171, HMR1586 or those asdescribed in WO2005097738.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Omacor® (omega-3 fatty acids; highlyconcentrated ethyl esters of eicosapentaenoic acid and ofdocosahexaenoic acid).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor such as, for example,avasimibe.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant such as, for example,OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin such as, for example, vitaminB6 or vitamin B12.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator such as,for example, ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP citrate lyase inhibitor such as,for example, SB-204990.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor suchas, for example, BMS-188494 or as described in WO2005077907.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist such as,for example, gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an HM74A receptor agonist such as, forexample, nicotinic acid.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor such as, forexample, orlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a sulfonylurea such as, for example,tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a biguanide such as, for example,metformin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a meglitinide such as, for example,repaglinide or nateglinide.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a thiazolidinedione such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone or thecompounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an α-glucosidase inhibitor such as, forexample, miglitol or acarbose.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an active ingredient which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment of the invention, the compound of the formula I isadministered in combination with more than one of the aforementionedcompounds, e.g. in combination with a sulfonylurea and metformin, asulfonylurea and acarbose, repaglinide and metformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of glycogen phosphorylase,such as, for example, PSN-357 or FR-258900 or those as described inWO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.

In one embodiment of the invention, the compound of the formula I isadministered in combination with glucagon receptor antagonists such as,for example, A-770077, NNC-25-2504 or as described in WO2004100875 orWO2005065680.

In one embodiment of the invention, the compound of the formula I isadministered in combination with activators of glucokinase, such as, forexample, RO-4389620, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50or those as are described for example by Prosidion in WO2004072031,WO2004072066, WO 05103021 or WO 06016178, by Roche in WO 00058293, WO00183465, WO 00183478, WO 00185706, WO 00185707, WO 01044216, GB02385328, WO 02008209, WO 02014312, WO 0246173, WO 0248106, DE 10259786,WO 03095438, US 04067939 or WO 04052869, by Novo Nordisk in EP 1532980,WO 03055482, WO 04002481, WO 05049019, WO 05066145 or WO 05123132, byMerck/Banyu in WO 03080585, WO03097824, WO 04081001, WO 05063738 or WO05090332, by Eli Lilly in WO 04063194, or by Astra Zeneca in WO01020327, WO 03000262, WO 03000267, WO 03015774, WO 04045614, WO04046139, WO 05044801, WO 05054200, WO 05054233, WO 05056530, WO05080359, WO 05080360 or WO 05121110.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of gluconeogenesis, suchas, for example, FR-225654.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors offructose-1,6-bisphosphatase (FBPase), such as, for example, CS-917.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of glucose transporter 4(GLUT4), such as, for example, KST-48 (D.-O. Lee et al.:Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors ofglutamine-fructose-6-phosphate amidotransferase (GFAT), as are describedfor example in WO2004101528.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of dipeptidylpeptidase IV(DPP-IV), such as, for example, vildagliptin (LAF-237), sitagliptin(MK-0431), saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200, GW-825964× or as are described inWO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312,WO2005012308, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002,PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10 2005012873.4.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of 11-beta-hydroxysteroiddehydrogenase 1 (11β-HSD1), such as, for example, BVT-2733 or those asare described for example in WO200190090-94, WO200343999, WO2004112782,WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980,WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294,WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744,WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896,WO2005016877 or WO2005097759.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of protein tyrosinephosphatase 1B (PTP1B), as are described for example in WO200119830-31,WO200117516, WO2004506446, WO2005012295, PCT/EP2005/005311,PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP2005/or DE 10 2004 060542.4.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the sodium-dependentglucose transporter 1 or 2 (SGLT1, SGLT2), such as, for example,KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or as are describedfor example in WO2004007517, WO200452903, WO200452902,PCT/EP2005/005959, WO2005085237, JP2004359630 or by A. L. Handlon inExpert Opin. Ther. Patents (2005) 15(11), 1531-1540.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of hormone-sensitive lipase(HSL) as described for example in WO2005073199.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of acetyl-CoA carboxylase(ACC), such as, for example, those as described in WO199946262,WO200372197, WO2003072197 or WO2005044814.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of phosphoenolpyruvatecarboxykinase (PEPCK), such as, for example, those as described inWO2004074288.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of glycogen synthasekinase 3 beta (GSK-3 beta), as described for example in US2005222220,WO2005085230, PCT/EP2005/005346, WO2003078403, WO2004022544,WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984,WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442,WO2005087727 or WO2004046117.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of protein kinase C beta(PKC beta), such as, for example, ruboxistaurin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an endothelin A receptor antagonistsuch as, for example, avosentan (SPP-301).

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of “I-kappaB kinase” (IKKinhibitors), as are described for example in WO2001000610, WO2001030774,WO2004022553 or WO2005097129.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the glucocorticoidreceptor, like those described for example in WO2005090336.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with CART modulators (see“Cocaine-amphetamine-regulated transcript influences energy metabolism,anxiety and gastric emptying in mice” Asakawa, A. et al.: Hormone andMetabolic Research (2001), 33(9), 554-558);

NPY antagonists such as, for example, naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amidehydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) or analogouscompounds, such as, for example, CJC-1682 (PYY3-36 conjugated with humanserum albumin via Cys34), CJC-1643 (derivative of PYY3-36 whichconjugates in vivo to serum albumin) or those as are described inWO2005080424;cannabinoid receptor 1 antagonists such as, for example, rimonabant,SR147778 or those as are described for example in EP 0656354, WO00/15609, WO02/076949, WO2005080345, WO2005080328, WO2005080343,WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776,WO2003040107, WO2003007887, WO2003027069, U.S. Pat. No. 6,509,367,WO200132663, WO2003086288, WO2003087037, WO2004048317, WO2004058145,WO2003084930, WO2003084943, WO2004058744, WO2004013120, WO2004029204,WO2004035566, WO2004058249, WO2004058255, WO2004058727, WO2004069838,US20040214837, US20040214855, US20040214856, WO2004096209, WO2004096763,WO2004096794, WO2005000809, WO2004099157, US20040266845, WO2004110453,WO2004108728, WO2004000817, WO2005000820, US20050009870, WO200500974,WO2004111033-34, WO200411038-39, WO2005016286, WO2005007111,WO2005007628, US20050054679, WO2005027837, WO2005028456,WO2005063761-62, WO2005061509 or WO2005077897;MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylicacid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141 or those that are described in WO2005060985,WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720,US20050124652, WO2005051391, WO2004112793, WOUS20050222014,US20050176728, US20050164914, US20050124636, US20050130988,US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109,WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339,EP1460069, WO2005047253, WO2005047251, EP1538159, WO2004072076 orWO2004072077;orexin receptor antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A) or those as are described for example in WO200196302,WO200185693, WO2004085403 or WO2005075458);histamine H3 receptor agonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208) or those as are described in WO200064884,WO2005082893);CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585));CRF BP antagonists (e.g. urocortin);urocortin agonists;β3 agonists (such as, for example,1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451));MSH (melanocyte-stimulating hormone) agonists;MCH (melanin-concentrating hormone) receptor antagonists (such as, forexample, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71,GW-803430 or compounds such as are described in WO2003/15769,WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769,WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2003033476,WO2002006245, WO2002002744, WO2003004027 or FR2868780);CCK-A agonists (such as, for example,{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclo-hexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525), SR-146131 (WO 0244150) orSSR-125180);serotonin reuptake inhibitors (e.g. dexfenfluramine);mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549);5-HT receptor agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalicacid salt (WO 01/09111);5-HT2C receptor agonists (such as, for example, APD-356, BVT-933 orthose as are described in WO200077010, WO20077001-02, WO2005019180,WO2003064423, WO200242304 or WO2005082859);5-HT6 receptor antagonists as are described for example in WO2005058858;bombesin receptor agonists (BRS-3 agonists);galanin receptor antagonists;growth hormone (e.g. human growth hormone or AOD-9604);growth hormone-releasing compounds (tertiary butyl6-benzyloxy-1-(2-diisopropyl-aminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695));growth hormone secretagogue receptor antagonists (ghrelin antagonists)such as, for example, A-778193 or those as are described inWO2005030734;TRH agonists (see, for example, EP 0 462 884);uncoupling protein 2 or 3 modulators;leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881);DA agonists (bromocriptine or Doprexin);lipase/amylase inhibitors (like those described for example in WO00/40569);inhibitors of diacylglycerol O-acyltransferases (DGATs) as described forexample in US2004/0224997, WO2004094618, WO200058491, WO2005044250,WO2005072740, JP2005206492 or WO2005013907;inhibitors of fatty acid synthase (FAS) such as, for example, C75 orthose as described in WO2004005277;oxyntomodulin;oleoyl-estroneor thyroid hormone receptor agonists such as, for example: KB-2115 orthose as described in WO20058279, WO200172692, WO200194293,WO2003084915, WO2004018421 or WO2005092316.

In one embodiment of the invention, the further active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment of the invention, the further active ingredient isdexamphetamine or amphetamine.

In one embodiment of the invention, the further active ingredient isfenfluramine or dexfenfluramine.

In another embodiment of the invention, the further active ingredient issibutramine.

In one embodiment of the invention, the further active ingredient ismazindole or phentermine.

In one embodiment of the invention, the compound of the formula I isadministered in combination with bulking agents, preferably insolublebulking agents (see, for example, Carob/Caromax® (Zunft H J; et al.,Carob pulp preparation for treatment of hypercholesterolemia, ADVANCESIN THERAPY (2001 September-October), 18(5), 230-6). Caromax is acarob-containing product from Nutrinova, Nutrition Specialties & FoodIngredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main).Combination with Caromax® is possible in one preparation or by separateadministration of compounds of the formula I and Caromax®. Caromax® canin this connection also be administered in the form of food productssuch as, for example, in bakery products or muesli bars.

It will be understood that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more further pharmacologically active substances willbe regarded as falling within the protection conferred by the presentinvention.

The invention further relates both to mixtures of stereoisomers of theformula I and to the pure stereoisomers of the formula I, and mixturesof diastereomers of the formula I and the pure diastereomers. Separationof the mixtures takes place chromatographically.

The examples detailed below serve to illustrate the invention without,however, restricting it.

TABLE 1 I

Ex. R1 R6 R7 R8 R9 R10 X m Linkage 1 H H H F H H —(CH₂)₂— 0 5 2 H H CF₃H H H —(CH₂)₂— 0 5 3 H H H CF₃ H H —(CH₂)₂— 0 5 4 H H CF₃ H CF₃ H—(CH₂)₂— 0 5 5 H H H NEt₂ H H —(CH₂)₂— 0 5 6 H CN H H H H —(CH₂)₂— 0 5 7H H H SO₂NH₂ H H —(CH₂)₂— 0 5 8 H H H OCHF₂ H H —(CH₂)₂— 0 5 9 H Ph H HH H —(CH₂)₂— 0 5 10 H H H SO₂—N-Pip H H —(CH₂)₂— 0 5 11 H H H SO₂—N-PipH H —(CH₂)₂— 0 5 12 H CF₃ H H H H —(CH₂)₂— 0 5 13 H F H F H H —(CH₂)₂— 05 14 H F H F H F —(CH₂)₂— 0 5 15 H F H H H F —(CH₂)₂— 0 5 16 H H CF₃ H HCl —(CH₂)₂— 0 5 17 H H CN H H H —(CH₂)₂— 0 5 18 H H Cl H H OMe —(CH₂)₂—0 5 19 H H OMe OMe H H —(CH₂)₂— 0 5 20 H H OMe OMe OMe H —(CH₂)₂— 0 5 21H H Ph H H OMe —(CH₂)₂— 0 5 22 H H H OCH₂Ph H H —(CH₂)₂— 0 5 23 H H CO₂HH H H —(CH₂)₂— 0 5 24 H H H CO₂H H H —(CH₂)₂— 0 5 25 H H H OCF₃ H H—(CH₂)₂— 0 5 26 H H OCH₂Ph H H H —(CH₂)₂— 0 5 27 H H H OPh H H —(CH₂)₂—0 5 28 H OCF₃ H H H H —(CH₂)₂— 0 5 29 H CF₃ H Cl H H —(CH₂)₂— 0 5 30 H HH SCF₃ H H —(CH₂)₂— 0 5 31 H H SCF₃ H H H —(CH₂)₂— 0 5 32 H H CF₃ H H F—(CH₂)₂— 0 5 33 H OCHF₂ H H H H —(CH₂)₂— 0 5 34 H Me H H H Me —(CH₂)₂— 05 35 H Br H Me H H —(CH₂)₂— 0 5 36 H H Br H H Br —(CH₂)₂— 0 5 37 H F F FF F —(CH₂)₂— 0 5 38 H H H Br H H —(CH₂)₂— 0 5 39 H H H N(Et)—(CH₂)₂—OH HH —(CH₂)₂— 0 5 40 H H H (CH₂)₂—OH H H —(CH₂)₂— 0 5 41 H H H NMe₂ H H—(CH₂)₂— 0 5 42 H H H SO₃H H H —(CH₂)₂— 0 5 43 H F F H F F —(CH₂)₂— 0 544 H H F H H F —(CH₂)₂— 0 5 45 H Cl Cl H H H —(CH₂)₂— 0 5 46 H Cl Cl ClH H —(CH₂)₂— 0 5 47 H H Cl Cl H Cl —(CH₂)₂— 0 5 48 H Cl H Cl H Cl—(CH₂)₂— 0 5 49 H H Cl H H Cl —(CH₂)₂— 0 5 50 H H OMe H H OMe —(CH₂)₂— 05 51 H SMe H H H H —(CH₂)₂— 0 5 52 H Me Me H H H —(CH₂)₂— 0 5 53 H H MeMe H Me —(CH₂)₂— 0 5 54 H Et H H H H —(CH₂)₂— 0 5 55 H Me H H H Et—(CH₂)₂— 0 5 56 H Et H H H Et —(CH₂)₂— 0 5 57 H H Cl H Cl H —(CH₂)₂— 0 558 H H CO₂Me H H H —(CH₂)₂— 0 5 59 H H Me H Me H —(CH₂)₂— 0 5 60 H OMe HH Me H —(CH₂)₂— 0 5 61 H —CH═CH—CH═CH— H H H —(CH₂)₂— 0 5 62 H—CH═CH—CH═CH— NMe₂ H H —(CH₂)₂— 0 5 63 H H H H H H —(CH₂)₂— 0 5 64 H F HH H H —(CH₂)₂— 0 5 65 H Cl H H H H —(CH₂)₂— 0 5 66 H Me H H H H —(CH₂)₂—0 5 67 H H F H H H —(CH₂)₂— 0 5 68 H H Cl H H H —(CH₂)₂— 0 5 69 H H Me HH H —(CH₂)₂— 0 5 70 H H H Cl H H —(CH₂)₂— 0 5 71 H H H Me H H —(CH₂)₂— 05 72 H OMe H H H H —(CH₂)₂— 0 5 73 H H H OMe H H —(CH₂)₂— 0 5 74 H i-PrH H H H —(CH₂)₂— 0 5 75 H Me H Me H Me —(CH₂)₂— 0 5 76 H Me Cl H H H—(CH₂)₂— 0 5 77 H H Cl Me H H —(CH₂)₂— 0 5 78 H H H CO₂Et H H —(CH₂)₂— 05 79 H H H t-Bu H H —(CH₂)₂— 0 5 80 H H H i-Pr H H —(CH₂)₂— 0 5 81 H HMe Me H H —(CH₂)₂— 0 5 82 H Cl H Cl H H —(CH₂)₂— 0 5 83 H H Cl Cl H H—(CH₂)₂— 0 5 84 H Br H H H H —(CH₂)₂— 0 5 85 H H Br H H H —(CH₂)₂— 0 586 H H Cl Br H H —(CH₂)₂— 0 5 87 H H Ac H H H —(CH₂)₂— 0 5 88 H Me H BrH Me —(CH₂)₂— 0 5 89 H H F Me H H —(CH₂)₂— 0 5 90 H H F F H H —(CH₂)₂— 05 91 H Cl H CF₃ H H —(CH₂)₂— 0 5 92 H H CH₂OH H H H —(CH₂)₂— 0 5 93 H HCH(OH)—CH₃ H H H —(CH₂)₂— 0 5 94 H Cl H F H H —(CH₂)₂— 0 5 95 H F H Cl HH —(CH₂)₂— 0 5 96 H H Me Cl H H —(CH₂)₂— 0 5 97 H Br H Br H H —(CH₂)₂— 05 98 H H F F H F —(CH₂)₂— 0 5 99 H F F H F H —(CH₂)₂— 0 5 100 H Me F H HH —(CH₂)₂— 0 5 101 H Br H CF3 H H —(CH₂)₂— 0 5 102 H F Cl H H H —(CH₂)₂—0 5 103 H H Me F H H —(CH₂)₂— 0 5 104 H H OMe Cl H OMe —(CH₂)₂— 0 5 105H H —(CH₂)₃— H H —(CH₂)₂— 0 5 106 H Me H OMe H H —(CH₂)₂— 0 5 107 H H ClOMe H OMe —(CH₂)₂— 0 5 108 H H Cl F H H —(CH₂)₂— 0 5 109 H H —O—CH₂—O— HH —(CH₂)₂— 0 5 110 H H Et H H H —(CH₂)₂— 0 5 111 H H H CN H H —(CH₂)₂— 05 112 H Me H Cl H H —(CH₂)₂— 0 5 113 H H CF₃ Cl H H —(CH₂)₂— 0 5 114 H HH OEt H H —(CH₂)₂— 0 5 115 H H H CO₂Me H H —(CH₂)₂— 0 5 116 H H H Ac H H—(CH₂)₂— 0 5 117 H H H Et H H —(CH₂)₂— 0 5 118 H H H n-Bu H H —(CH₂)₂— 05 119 H H H SMe H H —(CH₂)₂— 0 5 120 H OEt H H H H —(CH₂)₂— 0 5 121 H MeH H Me H —(CH₂)₂— 0 5 122 H H Cl H H Me —(CH₂)₂— 0 5 123 H Me H F H H—(CH₂)₂— 0 5 124 H H —O—(CH₂)₂—O H H —(CH₂)₂— 0 5 125 H H F H H Br—(CH₂)₂— 0 5 126 H Br H F H H —(CH₂)₂— 0 5 127 H H OH H H H —(CH₂)₂— 0 5128 H Cl H Cl H Me —(CH₂)₂— 0 5 129 H Br H i-Pr H H —(CH₂)₂— 0 5 130 H HCl H H F —(CH₂)₂— 0 5 131 H H F H F H —(CH₂)₂— 0 5 132 H F F F H H—(CH₂)₂— 0 5 133 H H Cl OH Cl H —(CH₂)₂— 0 5 134 H F H Br H H —(CH₂)₂— 05 135 H H CF₃ F H H —(CH₂)₂— 0 5 136 H H CF₃ Me H H —(CH₂)₂— 0 5 137 H HMe OH Me H —(CH₂)₂— 0 5 138 H Cl Cl H Cl Cl —(CH₂)₂— 0 5 139 H OCHF₂ HMe H H —(CH₂)₂— 0 5 140 H OCHF₂ H H Me H —(CH₂)₂— 0 5 141 H F H Me H H—(CH₂)₂— 0 5 142 H F H H Me H —(CH₂)₂— 0 5 143 H CO₂H H H H H —(CH₂)₂— 05 144 H Cl Cl H H H —(CH₂)₂— 0 6 145 H CF₃ H Cl H H —(CH₂)₂— 0 6 146 HCl H CF₃ H H —(CH₂)₂— 0 5

The activity of the compounds was tested as follows:

In Vitro FLIPR Assay with Recombinant Cells which Express the GPCR GPR40

Function-testing assays were carried out by means of the FLIPR technique(“Fluorescence Imaging Plate Reader”, Molecular Devices Corp.). For thispurpose, agonist-induced changes in the intracellular concentration ofCa²⁺ in recombinant HEK293 cells which expressed the GPCR GPR40 weredetermined.

For the investigations, cells were seeded in 96-well microliter plates(60 000 cells/well) and allowed to grow overnight. The medium wasremoved and the cells were incubated in buffer which contained thefluorescent dye fluo-4. After this loading with dye, the cells werewashed, test substance was added, and changes in the intracellular Ca²⁺concentration were measured in the FLIPR instrument. Results have beenpresented as percentage change relative to the control (0%: no testsubstance added; 100%: 10 μM reference agonist linoleic acid added).

TABLE 2 Biological activity % activation Ex. @ 100 μM 29 92 36 97 45 11148 111 82 90 91 100 97 96 101 96 129 89 138 100 144 87 145 79

It is evident from the table that the compounds of the formula Iactivate the GPR40 receptor and thus are very suitable for the treatmentof hyperglycemia and of diabetes. Insulin release is increased by thecompounds of the formula I (see Itoh et al., Nature 2003, 422, 173-176).

The compounds of the formula I may also show a corresponding effect onthe GPR120 receptor.

The compounds of the formula I can be prepared for example by reactingsuitable starting materials of the formula II (the syntheses aresufficiently well known in the literature) with isothiocyanates of theformula III to give compounds of the formula IV.

This process is adequately described in the literature.

The compounds of the formula I can be prepared for example by convertingsuitable starting materials (in the case of substituted(2-hydroxyphenyl)thioureas) of the formula IV (the syntheses aresufficiently well known in the literature) by a choice of a suitabledesulfurizing reagent such as, for example, yellow HgO (Journal ofChemical Research, Synopses 2001, (4), 138-139), PbO (Journal ofPharmaceutical Sciences 1964, 53 (5), 538-44), AgNO₃/NH₄OH (KhimiyaGeterotsiklicheskikh Soedinenii 1981, (5), 604-7), KO₂ (ChemistryLetters 1986, (8), 1291-4), N,N′-dicyclohexylcarbonyldiimide (DE3006671), methyl iodide/s-collidine (Tetrahedron Letters 2001, 42 (34),5853-5856), or p-toluenesulfonyl chloride/NaOH (Tetrahedron 2004, 60,9883-9888) into the corresponding 2-aminobenzoxazoles of the formula I.

The compounds of the formula I can also be converted by the synthesisdescribed by Jong Yeon Hwang and Young-Dae Gong (J. Comb. Chem. 2006, inpress) of polymer-bound mercaptobenzoxazoles by reacting 2-aminophenolsof the formula II with CS₂ and for example Merrifield resin in thepresence of diisopropylcarbonyldiimide into the compounds of the formulaV,

subsequent oxidation of the sulfur to the sulfone and reaction withanilines of the formula VI afford compounds of the formula I.

The general preparation of the examples is described in detail below:

Experimental Section: General Experimental Protocol:

0.25 mmol of an aminophenol is dissolved in 1.5 ml of 4:1toluene/dimethylformamide, and 0.275 mmol of the appropriate isocyanateis added. The mixture is then heated at 80° C. with stirring for 1 hour.After complete conversion into the thiourea, 0.375 mmol of yellow HgO isadded and stirring is continued at 80° C. for 2 hours. After conversionis complete, the mixture is cooled and mixed with 0.3 g of thiolscavenger (SiO₂-bound propane thiol, Aldrich) and stirred at roomtemperature for a further 12 hours. It is then filtered through Celite,concentrated and purified by preparative HPLC (Waters C₁₈, X-Terra, 10μm, 30×100 mm, acetonitrile/(water+0.1% TFA), 10% acetonitrile to 90% in4 minutes). The compounds were analyzed by LC/MS. The appropriatemolecular peak (M+H) was detectable by LC/MS with all the examples.

We claim:
 1. A compound of formula I,

wherein: R1 is H or (C₁-C₆)-alkyl; R6, R7, R8, R9 and R10 are,independently of one another, H, F, Cl, Br, CN, CF₃, OH, OCF₃, OCHF₂,SCH₃, SCF₃, phenyl, O-phenyl, COOH, COO—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, OBn, SO₃H, SO₂NR3R4, NR3R4 orSO₂—N-piperidinyl, wherein the alkyl and phenyl moieties are optionallysubstituted one or more times by R2, or two of the radicals R6, R7, R8,R9 and R10, in adjacent position on the phenyl ring may together form aradical —O—CH₂—O—, —O—(CH₂)₂—O— or —CH═CH—CH═CH—; m is 0, 1, 2 or 3; Xis bond, (C₂-C₁₀)-alkylene, (C₃-C₁₂)-cycloalkyl,(C₁-C₈)-alkylene-(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkylene,(C₁-C₈)-alkylene-(C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkylene,(C₂-C₈)-alkenylene-(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkylene,(C₁-C₈)-alkylene-(C₃-C₁₂)-cycloalkyl-(C₂-C₈)-alkenylene,(C₂-C₈)-alkenylene-(C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₂-C₈)-alkenylene, (C₂-C₁₀)-alkenylene or(C₂-C₁₀)-alkynylene, wherein the alkylene, cycloalkyl, alkenylene andalkynylene moieties are optionally substituted one or more times by R5;R2 is OH, F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl orO—(C₁-C₆)-alkyl, wherein the alkyl moiety is optionally substituted oneor more times by OH, F, Cl, Br or CN; R3 and R4 are, independently ofone another, H or (C₁-C₆)-alkyl, wherein the alkyl is optionallysubstituted one or more times by OH, F, Cl or Br; and R5 is NH₂,NH(C₁-C₄)-alkyl, N[(C₁-C₄)-alkyl]₂, F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl,(C₁₋₆)-alkyl, (C₂-C₆)-alkenyl or (C₂-C₆)-alkynyl; or a physiologicallytolerated salt thereof.
 2. The compound according to claim 1, wherein:R6, R7, R8, R9 and R10 are, independently of one another, H, F, Cl, Br,CF₃, OCH₃, OCF₃, OCHF₂, SCH₃, SCF₃, phenyl, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl or NR3R4, wherein the alkyl and phenyl moieties areoptionally substituted one or more times by R2, or two of the radicalsR6, R7, R8, R9 and R10 in adjacent position on the phenyl ring maytogether form a radical —CH═CH—CH═CH—; X is (C₂-C₁₀)-alkylene, which isoptionally substituted one or more times by R5; R2 is F, Cl, Br, CN,OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl or O—(C₁-C₆)-alkyl, wherein thealkyl moiety is optionally substituted one or more times by OH, F, Cl,Br or CN; and R3 and R4 are, independently of one another, H or(C₁-C₆)-alkyl; or a physiologically tolerated salt thereof.
 3. Thecompound according to claim 1, wherein: R1 is H; R6, R7, R8, R9 and R10are, independently of one another, H, F, Cl, Br, CF₃, OCH₃, OCF₃, OCHF₂,SCH₃, SCF₃, phenyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or NR3R4, wherein thealkyl and phenyl moieties are optionally substituted one or more timesby R2, or two of the radicals R6, R7, R8, R9 and R10 in adjacentposition on the phenyl ring may together form a radical —CH═CH—CH═CH—; Xis —(CH₂)₂—; R2 is F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl orO—(C₁-C₆)-alkyl, wherein the alkyl moiety is optionally substituted oneor more times by OH, F, Cl, Br or CN; and R3 and R4 are, independentlyof one another, H or (C₁-C₆)-alkyl; or a physiologically tolerated saltthereof.
 4. A pharmaceutical composition comprising the compoundaccording to claim 1 or a physiologically tolerated salt thereof, incombination with a pharmaceutically acceptable excipient.
 5. Apharmaceutical composition comprising the compound according to claim 2or a physiologically tolerated salt thereof, in combination with apharmaceutically acceptable excipient.
 6. A pharmaceutical compositioncomprising the compound according to claim 3 or a physiologicallytolerated salt thereof, in combination with a pharmaceuticallyacceptable excipient.
 7. The pharmaceutical composition according toclaim 4, further comprising at least one additional active ingredient.8. The pharmaceutical composition according to claim 5, furthercomprising at least one additional active ingredient.
 9. Thepharmaceutical composition according to claim 6, further comprising atleast one additional active ingredient.
 10. The pharmaceuticalcomposition according to claim 7, wherein the additional activeingredient is selected from the group consisting of antidiabetics,hypoglycemic active ingredients, HMGCoA reductase inhibitors,cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alphaagonists, PPAR alpha and gamma agonists, PPAR delta agonists, fibrates,MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors,polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors,antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyaseinhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists,HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas,biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors,active ingredients which act on the ATP-dependent potassium channel ofthe beta cells, glycogen phosphorylase inhibitors, glucagon receptorantagonists, activators of glucokinase, inhibitors of gluconeogenesis,inhibitors of fructose-1,6-bisphosphatase, modulators of glucosetransporter 4, inhibitors of glutamine-fructose-6-phosphateamidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosinephosphatase 1B, modulators of the sodium-dependent glucose transporter 1or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoAcarboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitorsof glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta,endothelin-A receptor antagonists, inhibitors of I kappaB kinase,modulators of the glucocorticoid receptor, CART agonists, NPY agonists,MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptorantagonists, MSH agonists, CCK agonists, serotonin reuptake inhibitors,mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptinagonists, DA agonists, lipase/amylase inhibitors, PPAR modulators, RXRmodulators or TR-β agonists and amphetamines.
 11. The pharmaceuticalcomposition according to claim 8, wherein the additional activeingredient is selected from the group consisting of antidiabetics,hypoglycemic active ingredients, HMGCoA reductase inhibitors,cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alphaagonists, PPAR alpha and gamma agonists, PPAR delta agonists, fibrates,MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors,polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors,antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyaseinhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists,HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas,biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors,active ingredients which act on the ATP-dependent potassium channel ofthe beta cells, glycogen phosphorylase inhibitors, glucagon receptorantagonists, activators of glucokinase, inhibitors of gluconeogenesis,inhibitors of fructose-1,6-bisphosphatase, modulators of glucosetransporter 4, inhibitors of glutamine-fructose-6-phosphateamidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosinephosphatase 1B, modulators of the sodium-dependent glucose transporter 1or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoAcarboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitorsof glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta,endothelin-A receptor antagonists, inhibitors of I kappaB kinase,modulators of the glucocorticoid receptor, CART agonists, NPY agonists,MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptorantagonists, MSH agonists, CCK agonists, serotonin reuptake inhibitors,mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptinagonists, DA agonists, lipase/amylase inhibitors, PPAR modulators, RXRmodulators or TR-(3 agonists and amphetamines.
 12. The pharmaceuticalcomposition according to claim 9, wherein the additional activeingredient is selected from the group consisting of antidiabetics,hypoglycemic active ingredients, HMGCoA reductase inhibitors,cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alphaagonists, PPAR alpha and gamma agonists, PPAR delta agonists, fibrates,MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors,polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors,antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyaseinhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists,HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas,biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors,active ingredients which act on the ATP-dependent potassium channel ofthe beta cells, glycogen phosphorylase inhibitors, glucagon receptorantagonists, activators of glucokinase, inhibitors of gluconeogenesis,inhibitors of fructose-1,6-bisphosphatase, modulators of glucosetransporter 4, inhibitors of glutamine-fructose-6-phosphateamidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosinephosphatase 1B, modulators of the sodium-dependent glucose transporter 1or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoAcarboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitorsof glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta,endothelin-A receptor antagonists, inhibitors of I kappaB kinase,modulators of the glucocorticoid receptor, CART agonists, NPY agonists,MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptorantagonists, MSH agonists, CCK agonists, serotonin reuptake inhibitors,mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptinagonists, DA agonists, lipase/amylase inhibitors, PPAR modulators, RXRmodulators or TR-β agonists and amphetamines.
 13. A method for loweringblood glucose, treating diabetes, or increasing insulin release, in apatient in need thereof, comprising administering to the patient apharmaceutically effective amount of the compound according to claim 1,or a physiologically tolerated salt thereof.
 14. A method for loweringblood glucose, treating diabetes, or increasing insulin release, in apatient in need thereof, comprising administering to the patient apharmaceutically effective amount of the compound according to claim 2,or a physiologically tolerated salt thereof.
 15. A method for loweringblood glucose, treating diabetes, or increasing insulin release, in apatient in need thereof, comprising administering to the patient apharmaceutically effective amount of the compound according to claim 3,or a physiologically tolerated salt thereof.
 16. A process formanufacturing a pharmaceutical composition comprising the compoundaccording to claim 1 or a physiologically tolerated salt thereof, incombination with a pharmaceutically acceptable excipient, whichcomprises mixing the compound according to claim 1 or thephysiologically tolerated salt thereof, with the pharmaceuticallyacceptable excipient, and converting this mixture into a form suitablefor administration.
 17. A process for manufacturing a pharmaceuticalcomposition comprising the compound according to claim 2 or aphysiologically tolerated salt thereof, in combination with apharmaceutically acceptable excipient, which comprises mixing thecompound according to claim 2 or the physiologically tolerated saltthereof, with the pharmaceutically acceptable excipient, and convertingthis mixture into a form suitable for administration.
 18. A process formanufacturing a pharmaceutical composition comprising the compoundaccording to claim 3 or a physiologically tolerated salt thereof, incombination with a pharmaceutically acceptable excipient, whichcomprises mixing the compound according to claim 3 or thephysiologically tolerated salt thereof, with the pharmaceuticallyacceptable excipient, and converting this mixture into a form suitablefor administration.